Special Warning : אזהרת שימוש

4.4     Special warnings and precautions for use

Embryo-foetal death or severe birth defects
Erivedge may cause embryo-foetal death or severe birth defects when administered to a pregnant woman (see section 4.6). Hedgehog pathway inhibitors, (see section 5.1) such as vismodegib, have been demonstrated to be embryotoxic and/or teratogenic in multiple animal species and can cause severe malformations, including craniofacial anomalies, midline defects and limb defects (see section 5.3). Erivedge must not be used during pregnancy (see section 4.3).

Criteria for a woman of childbearing potential (WCBP)
A WCBP is defined in the Erivedge Pregnancy Prevention Programme as:
•     a sexually mature female who •      has menstruated at any time during the previous 12 consecutive months, •      has not undergone a hysterectomy or a bilateral oophorectomy, or who does not have medically-confirmed permanent premature ovarian failure,
•      does not have a XY genotype, Turner’s syndrome, or uterine agenesis, •      becomes amenorrhoeic following cancer therapy, including treatment with Erivedge.

Counselling
For a WCBP
Erivedge is contraindicated in a WCBP who does not comply with the Erivedge Pregnancy Prevention Programme.
A WCBP must understand that:
•     Erivedge exposes a teratogenic risk to the unborn child,
•     She must not take Erivedge if she is pregnant or plans to become pregnant,
•     She must have a negative pregnancy test, conducted by a health care provider within 7 days before starting Erivedge treatment,
•     She must have a negative pregnancy test monthly during treatment, even if she has become amenorrhoeic,
•     She must not become pregnant while taking Erivedge and for 24 months after her final dose,
•     She must be able to comply with effective contraceptive measures,
•     She must use 2 methods of recommended contraception (see the ‘Contraception' section below and section 4.6) while she is taking Erivedge, unless she commits to not having sexual intercourse (abstinence),
•     She must tell her healthcare provider if any of the following occur during treatment and for       24 months after her final dose:
•     If she becomes pregnant or think for any reason that she may be pregnant, •     If she misses her expected menstrual period,
•     If she stops using contraception unless she commits to not having sexual intercourse (abstinence),
•     If she needs to change contraception during treatment,
•     She must not breast-feed while taking Erivedge and for 24 months after the final dose.

For men
Vismodegib is present in semen. To avoid potential foetal exposure during pregnancy, a male patient must understand that:
•     Erivedge exposes a teratogenic risk to the unborn child if he engages in unprotected sexual activity with a pregnant woman,

•     He must always use the recommended contraception (see the ‘Contraception' section below and section 4.6),
•     He will tell his healthcare provider if his female partner becomes pregnant while he is taking Erivedge or during the 2 months after his final dose.

For health care providers (HCP)
HCPs must educate the patients so they understand and acknowledge all the conditions of the Erivedge Pregnancy Prevention Programme.

Contraception
WCBP
Female patients must use two methods of recommended contraception including one highly effective method and a barrier method during Erivedge therapy and for 24 months after the final dose (see section 4.6).

Men
Male patients must always use a condom (with spermicide, if available), even after a vasectomy, when having sex with a female partner while taking Erivedge and for 2 months after the final dose (see section 4.6).

Pregnancy testing
In a WCBP, a medically supervised pregnancy test, conducted by a health care provider, should be performed within 7 days prior to initiating treatment and monthly during treatment. Pregnancy tests should have a minimum sensitivity of 25 mIU/mL as per local availability. Patients who present with amenorrhoea during treatment with Erivedge should continue monthly pregnancy testing while on treatment.

Prescribing and dispensing restrictions for WCBP
The initial prescription and dispensing of Erivedge should occur within a maximum of 7 days of a negative pregnancy test (day of pregnancy test = day 1). Prescriptions of Erivedge should be limited to 28 days of treatment and continuation of treatment requires a new prescription.

Effects on post-natal development
Premature fusion of the epiphyses and precocious puberty have been reported in paediatric patients exposed to Erivedge. Due to the long drug elimination half-life, these events may occur or progress after drug discontinuation. In animal species, vismodegib has been shown to cause severe irreversible changes in growing teeth (degeneration/necrosis of odontoblasts, formation of fluid-filled cysts in the dental pulp, ossification of the root canal, and haemorrhage) and closure of the epiphyseal growth plate. The findings of premature fusion of the epiphyses indicate a potential risk for short stature and tooth deformities to infants and children (see section 5.3).

Blood donation
Patients should not donate blood while taking Erivedge and for 24 months after the final dose.

Semen donation
Male patients should not donate semen while taking Erivedge and for 2 months after the final dose.
Interactions
Concomitant treatment with strong CYP inducers (e.g. rifampicin, carbamazepine or phenytoin) should be avoided, as a risk for decreased plasma concentrations and decreased efficacy of vismodegib cannot be excluded (see also section 4.5).

Severe cutaneous adverse reactions
Severe cutaneous adverse reactions (SCARs) including cases of Stevens-Johnson syndrome/Toxic epidermal necrolysis (SJS/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalised exanthematous pustulosis (AGEP), which can be life-threatening, have been reported during post-marketing use (see section 4.8). If the patient has developed any of these reactions with the use of vismodegib, treatment with vismodegib must not be restarted in this patient at any time.


Excipients
Erivedge capsules contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium free’.

Effects on Driving

4.7     Effects on ability to drive and use machines
Erivedge has no or negligible influence on the ability to drive and use machines.